Ohmura K, Tamura G, Endoh Y, Sakata K, Takahashi T, Motoyama T
Department of Pathology, Yamagata University School of Medicine, Japan.
Hum Pathol. 2000 Sep;31(9):1031-5. doi: 10.1053/hupa.2000.16669.
To elucidate the relationship between genetic alterations and cellular phenotype of differentiated-type adenocarcinomas and precancerous lesions of the stomach, we phenotyped 61 gastric tumors consisting of 33 noninvasive lesions and 28 submucosal invasive carcinomas by histochemical and immunohistochemical techniques, including analysis of mucin expression. We then analyzed loss of heterozygosity (LOH) at tumor suppressor loci, examined microsatellite instability (MSI), and compared the results according to cellular phenotype. Of the 61 gastric tumors studied, 7% (4 of 61) were classified as tumors with a gastric foveolar epithelial phenotype (foveolar-type), 8% (5 of 61) as tumors with a complete-type intestinal metaplastic phenotype (CIM-type), and the remaining 85% (52 of 61) as tumors with an ordinary phenotype (ordinary-type). Forty-two percent (26 of 61) of the tumors showed LOH on at least 1 chromosomal arm. Although LOH was rare in foveolar-type tumors, it was present at variable frequencies at each tumor suppressor loci in tumors with other cellular phenotypes. p53 overexpression was observed in 0% (0 of 4) of foveolar-type, 48% (25 of 52) of ordinary-type, and 80% (4 of 5) of CIM-type tumors. With regard to MSI, all (4 of 4) of the foveolar-type tumors were classified as having high-rate MSI (MSI-H), whereas all (5 of 5) of the CIM-type tumors were microsatellite stable (MSS). Of 52 ordinary-type tumors, 19% (10 of 52) were classified as MSI-H, 12% (6 of 52) as low-rate MSI (MSI-L), and 69% (36 of 52) as MSS. The incidence of MSI-H was found to be significantly higher in foveolar-type tumors (100%; 4 of 4) than in ordinary-type (19%; 10 of 52) or CIM-type tumors (0%; 0 of 5) (P < .01). An inverse correlation between MSI-H and p53 overexpression was also noticed (P < .01). Results suggested that each cellular phenotype followed a different genetic pathway; foveolar-type tumors followed the "mutator" pathway, characterized by MSI, CIM-type tumors followed the "suppressor" pathway, characterized by LOH of tumor suppressor loci and p53 overexpression, and ordinary-type tumors appeared to show mixed genetic alterations of both types.
为阐明胃分化型腺癌及癌前病变的基因改变与细胞表型之间的关系，我们采用组织化学和免疫组织化学技术，包括黏蛋白表达分析，对61例胃肿瘤进行了表型分析，其中包括33例非侵袭性病变和28例黏膜下浸润癌。然后，我们分析了肿瘤抑制基因座的杂合性缺失（LOH），检测了微卫星不稳定性（MSI），并根据细胞表型比较了结果。在所研究的61例胃肿瘤中，7%（61例中的4例）被分类为具有胃小凹上皮表型（小凹型）的肿瘤，8%（61例中的5例）为具有完全型肠化生表型（CIM型）的肿瘤，其余85%（61例中的52例）为具有普通表型（普通型）的肿瘤。42%（61例中的26例）的肿瘤在至少1条染色体臂上显示出LOH。虽然LOH在小凹型肿瘤中很少见，但在具有其他细胞表型的肿瘤中，每个肿瘤抑制基因座的LOH频率各不相同。在小凹型肿瘤中，p53过表达的发生率为0%（4例中的0例），普通型肿瘤为48%（52例中的25例），CIM型肿瘤为80%（5例中的4例）。关于MSI，所有（4例中的4例）小凹型肿瘤被分类为高频率MSI（MSI-H），而所有（5例中的5例）CIM型肿瘤微卫星稳定（MSS）。在52例普通型肿瘤中，19%（52例中的10例）被分类为MSI-H，12%（52例中的6例）为低频率MSI（MSI-L），69%（52例中的36例）为MSS。发现小凹型肿瘤中MSI-H的发生率（100%；4例中的4例）显著高于普通型（19%；52例中的10例）或CIM型肿瘤（0%；5例中的0例）（P <.01）。还注意到MSI-H与p53过表达之间呈负相关（P <.01）。结果表明，每种细胞表型遵循不同的遗传途径；小凹型肿瘤遵循以MSI为特征的“突变体”途径，CIM型肿瘤遵循以肿瘤抑制基因座的LOH和p53过表达为特征的“抑制”途径，普通型肿瘤似乎表现出两种类型的混合基因改变。
